Normal thyroid hormone signaling is essential for normal mammalian development and function after birth. Thyroid hormone (3,5,3'- triodothyronine or T3) signals through its cognate nuclear receptors (NRs), the thyroid hormone receptor (TR) isoforms which in turn are bound to either positive or negative thyroid hormone response elements (TREs). In the absence of its ligand the TR recruits the nuclear corepressors, N-CoR and SMRT, to mediate repression or silencing on positive TREs. The addition of ligand causes the TR binding complex to release the corepressor and recruit coactivators to mediate further gene activation. While N- CoR and SMRT have a similar modular structure and share significant amino acid homology they have significant differences that suggest they play distinct biologic roles. It is unclear which corepressor is important in thyroid hormone action but it is likely that one or both play critical roles in hypothyroidism and Resistance to Thyroid Hormone (RTH). An understanding of how the nuclear corepressors interact with T3 signaling pathways will shed light on the basic mechanisms by which the TRs regulate gene expression and on the role of the ligand-independent activity of the TR in human disease. The first Aim of this proposal will focus on the hypothesis that corepressor specificity exists and that the TR prefers to interact with N-CoR. The second Aim will explore the hypothesis that NCoR binding is able to influence TR complex binding and function which has ramifications for both positive and negative regulation as well as isoform specificity. The third Aim will employ mouse models which either lack NCoR itself, or express an inhibitor of corepressor function in multiple tissues, to explore the role of corepressors in hypothyroidism and RTH. Together, completion of these Aims will lend significant insight into the role of the nuclear corepressors on thyroid hormone action and establish a role for these proteins in thyroid disease.